Iohexol is a non-ionic iodinated X-ray contrast agent that has achieved considerable market success under the trade name OMNIPAQUE.RTM..
The manufacture of such non-ionic contrast agents involves the production of the chemical drug substance (referred to as primary production) followed by formulation into a drug product (referred to as secondary production). Primary production usually involves a multistep chemical synthesis and a thorough purification stage. Clearly for a commercial drug product it is important for the primary production stage to be efficient and economical.
The final step in iohexol production is an N-alkylation step in which 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (hereinafter "5-Acetamide") is reacted in the liquid phase with an alkylating agent to introduce the 2,3-dihydroxypropyl group at the nitrogen of the 5-acetamido group. Following this reaction, iohexol is isolated from the reaction mixture. This reaction is described for example in SE-7706792-4 where crude iohexol is obtained from the reaction between 5-Acetamide and 1-chloro-2,3-propanediol at ambient temperature in propylene glycol and in the presence of sodium methoxide. After repeated additions and evaporations of the propylene glycol solvent and treatment with anionic and cationic exchange resins, the crude product is evaporated to dryness and crystallized from a second solvent, butanol. The product is then recrystallized twice from butanol.
The N-alkylation step is problematic because of the possibility of by-product formation as a result of O-alkylation, and with N-alkylated iodinated X-ray contrast agents two or more crystallizations are often required in order to remove the O-alkylated by-products. If, as with the iohexol synthesis referred to above, the product is to be crystallized out from a second solvent system, the reaction solvent must first be removed, e.g. by evaporation to dryness or by extensive azeotropic distillation. However, as it is known from crystallization theory and experience that even small quantities of residual solvents from previous steps may cause a crystallization process to get out of control due to changes in supersaturation conditions, thorough removal of the reaction solvent is an important step. Solvent removal however is an energy consuming operation which also risks degradation of the product through prolonged exposure to elevated temperatures.